1. Field of the Invention
The invention relates to an improved method of synthesis of trans-2-phenylcyclopropylamine.
2. Background of the Prior Art
Methods for making 2-substituted cyclopropylamines such as 2-phenylcyclopropylamine are known, e.g. Kaiser et al, Journal of Medicinal and Pharmaceutical Chemistry, 5, 1243 (1962) and U.S. Pat. No. 2,997,422. In carrying out these prior art procedures, the trans isomer of 2-phenylcyclopropylamine is prepared by reacting styrene with ethyl diazoacetate to form the ester, cis,trans-ethyl 2-phenylcyclopropanecarboxylate, and the resulting ester is hydrolyzed to the cis,trans-2-phenylcyclopropane carboxylic acid. At this stage there are 3 to 4 parts of the trans isomer to 1 part of the cis isomer. A complete separation is accomplished by repeatedly recystallizing the acid from hot water. The pure trans isomer comes out as crystalline material while the cis isomer stays in solution. The trans-2-phenylcyclopropanecarboxylic acid is then reacted with thionyl chloride to form the acid chloride which is then successively treated with sodium azide and subjected to the Curtius degradation. The isocyanate formed by ths procedure is hydrolyzed readily to the trans-2-phenylcyclopropylamine. The foregoing process results in significant yield loss in that the cis isomer is discarded and significant amounts of trans isomer are lost in repeated recrystallizations. Furthermore, the trans isomer is contaminated by some cis isomer which results in an impure product.
Heretofore, trans-2-phenylcyclopropylamine has been used as a drug in the treatment of depression. Recently it was discovered that the (-)-enantiomer of trans-2-phenylcyclopropylamine was comparable in therapeutic effect to racemic (+)-trans 2-phenylcyclopropylamine, but had substantially fewer side effects. However, a problem related to the use of the (-)-trans isomer is that any cis impurity in the (-)-trans-2-phenylcyclopropylamine results in substantial lessening of the decrease in side effects. Therefore, it would be desirable to improve the present method of synthesis of trans-2-phenylcyclopropylamine to improve yield and purity.